Structural Insights into Thioether Bond Formation in the Biosynthesis of Sactipeptides

Sactipeptides are ribosomally synthesized peptides that contain a characteristic thioether bridge (sactionine bond) that is installed posttranslationally and is absolutely required for their antibiotic activity. Sactipeptide biosynthesis requires a unique family of radical SAM enzymes, which contain multiple [4Fe-4S] clusters, to form the requisite thioether bridge between a cysteine and the α-carbon of an opposing amino acid through radical-based chemistry. Here we present the structure of the sactionine bond-forming enzyme CteB, from Clostridium thermocellum ATCC 27405, with both SAM and an N-terminal fragment of its peptidyl-substrate at 2.04 Å resolution. CteB has the (β/α)6-TIM barrel fold that is characteristic of radical SAM enzymes, as well as a C-terminal SPASM domain that contains two auxiliary [4Fe-4S] clusters. Importantly, one [4Fe-4S] cluster in the SPASM domain exhibits an open coordination site in absence of peptide substrate, which is coordinated by a peptidyl-cysteine residue in the bound state. The crystal structure of CteB also reveals an accessory N-terminal domain that has high structural similarity to a recently discovered motif present in several enzymes that act on ribosomally synthesized and post-translationally modified peptides (RiPPs), known as a RiPP precursor peptide recognition element (RRE). This crystal structure is the first of a sactionine bond forming enzyme and sheds light on structures and mechanisms of other members of this class such as AlbA or ThnB

Acetogenin and Prenylated Flavonoids from Helminthostachys zeylanica with Inhibitory Activity on Superoxide Generation and Elastase Release by Neutrophils

One new acetogenin, 6-hydroxy-8-pentadecyloxocane-2,7-dione (1), and four new prenylated flavonoids, 4 '' a,5 '',6 '',7 '',8 '',8 '' a-hexahydro-5,3',4'-trihydroxy-5 '',5 '',8 '' a-trimethyl-4H-chromeno[2 '',3 '': 7,6] flavone (2), 4 '' a,5 '',6 '',7 '',8 '',8 '' a-hexahydro5,3', 4',-trihydroxy-5 '',5 '',8 '' a-trimethyl-4Hchromeno[2 '', 3 '': 7,8] flavone (3), 2-(3,4-dihydroxyphenyl)6-((2,2-dimethyl-6-methylenecyclohexyl) methyl)-5,7-dihydroxy-chroman-4-one (4), and 2-(3,4-dihydroxy-2-[(2,6,6-trimethylcyclohex-2-enyl) methyl] phenyl)-3,5,7-trihydroxy-4H-chromen-4-one (5), together with six known compounds, were isolated and purified from the rhizomes of Helminthostachys zeylanica by column chromatography and high performance liquid chromatography (HPLC) via bioactivity-guided fractionation isolation. The structures of the new isolates were elucidated by spectroscopic methods. Compounds 1, 3, and 5 showed inhibitory activities on either superoxide anion generation or elastase release by human neutrophils in response to formyl-L-methionyl-L-leucyl-L-phenylalanine/cytochalasin B (FMLP/CB)

BRST Analysis of Physical States for 2D (Super) Gravity Coupled to (Super) Conformal Matter

We summarize some recent results on the BRST analysis of physical states of 2D gravity coupled to c<=1 conformal matter and the supersymmetric generalization.Comment: 11 page

Geometric Approach to Pontryagin's Maximum Principle

Since the second half of the 20th century, Pontryagin's Maximum Principle has been widely discussed and used as a method to solve optimal control problems in medicine, robotics, finance, engineering, astronomy. Here, we focus on the proof and on the understanding of this Principle, using as much geometric ideas and geometric tools as possible. This approach provides a better and clearer understanding of the Principle and, in particular, of the role of the abnormal extremals. These extremals are interesting because they do not depend on the cost function, but only on the control system. Moreover, they were discarded as solutions until the nineties, when examples of strict abnormal optimal curves were found. In order to give a detailed exposition of the proof, the paper is mostly self\textendash{}contained, which forces us to consider different areas in mathematics such as algebra, analysis, geometry.Comment: Final version. Minors changes have been made. 56 page

E-retailing ethics in Egypt and its effect on customer repurchase intention

The theoretical understanding of online shopping behaviour has received much attention. Less focus has been given to the formation of the ethical issues that result from online shopper interactions with e-retailers. The vast majority of earlier research on this area is conceptual in nature and limited in scope by focusing on consumers’ privacy issues. Therefore, the purpose of this paper is to propose a theoretical model explaining what factors contribute to online retailing ethics and its effect on customer repurchase intention. The data were analysed using variance-based structural equation modelling, employing partial least squares regression. Findings indicate that the five factors of the online retailing ethics (security, privacy, non- deception, fulfilment/reliability, and corporate social responsibility) are strongly predictive of online consumers’ repurchase intention. The results offer important implications for e-retailers and are likely to stimulate further research in the area of e-ethics from the consumers’ perspective

Trans-ancestry genome-wide association study identifies 12 genetic loci influencing blood pressure and implicates a role for DNA methylation

We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 &times; 10-11 to 5.0 &times; 10-21). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 &times; 10-6). Our results provide new evidence for the role of DNA methylation in blood pressure regulation